NM_000249.4(MLH1):c.67dup (p.Glu23fs) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 14, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000686674.6

Allele description [Variation Report for NM_000249.4(MLH1):c.67dup (p.Glu23fs)]

NM_000249.4(MLH1):c.67dup (p.Glu23fs)

Gene:

MLH1:mutL homolog 1 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.67dup (p.Glu23fs)

HGVS:

NC_000003.12:g.36993614dup
NG_007109.2:g.5265dup
NG_008418.1:g.4695dup
NM_000249.4:c.67dupMANE SELECT
NM_001167617.3:c.-450dup
NM_001167618.3:c.-879dup
NM_001167619.3:c.-792dup
NM_001258271.2:c.67dup
NM_001258273.2:c.-566dup
NM_001258274.3:c.-1029dup
NM_001354615.2:c.-560dup
NM_001354616.2:c.-560dup
NM_001354617.2:c.-652dup
NM_001354618.2:c.-884dup
NM_001354619.2:c.-1008dup
NM_001354620.2:c.-218dup
NM_001354621.2:c.-977dup
NM_001354622.2:c.-1090dup
NM_001354623.2:c.-999dup
NM_001354624.2:c.-760dup
NM_001354625.2:c.-658dup
NM_001354626.2:c.-755dup
NM_001354627.2:c.-987dup
NM_001354628.2:c.67dup
NM_001354629.2:c.67dup
NM_001354630.2:c.67dup
NP_000240.1:p.Glu23fs
NP_000240.1:p.Glu23fs
NP_001245200.1:p.Glu23fs
NP_001341557.1:p.Glu23fs
NP_001341558.1:p.Glu23fs
NP_001341559.1:p.Glu23fs
LRG_216t1:c.67dup
LRG_216:g.5265dup
LRG_216p1:p.Glu23fs
NC_000003.11:g.37035100_37035101insG
NC_000003.11:g.37035105dup
NM_000249.3:c.67dup
NM_000249.3:c.67dupG

Protein change:

E23fs

Links:

dbSNP: rs63750822

NCBI 1000 Genomes Browser:

rs63750822

Molecular consequence:

NM_001167617.3:c.-450dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-879dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-792dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-566dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-1029dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-560dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-560dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-652dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-884dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-1008dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-218dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-977dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-1090dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-999dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-760dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-658dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-755dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-987dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.67dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258271.2:c.67dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354628.2:c.67dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354629.2:c.67dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354630.2:c.67dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Hereditary nonpolyposis colorectal neoplasms
Identifiers:: MeSH: D003123; MedGen: C0009405

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000814202	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 14, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15713769, 24362816, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000814202

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 14, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer.

Casey G, Lindor NM, Papadopoulos N, Thibodeau SN, Moskow J, Steelman S, Buzin CH, Sommer SS, Collins CE, Butz M, Aronson M, Gallinger S, Barker MA, Young JP, Jass JR, Hopper JL, Diep A, Bapat B, Salem M, Seminara D, Haile R; Colon Cancer Family Registry..

JAMA. 2005 Feb 16;293(7):799-809.

PubMed [citation]

PMID:: 15713769
PMCID:: PMC2933041

Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.

Thompson BA, Spurdle AB, Plazzer JP, Greenblatt MS, Akagi K, Al-Mulla F, Bapat B, Bernstein I, Capellá G, den Dunnen JT, du Sart D, Fabre A, Farrell MP, Farrington SM, Frayling IM, Frebourg T, Goldgar DE, Heinen CD, Holinski-Feder E, Kohonen-Corish M, Robinson KL, Leung SY, et al.

Nat Genet. 2014 Feb;46(2):107-115. doi: 10.1038/ng.2854. Epub 2013 Dec 22.

PubMed [citation]

PMID:: 24362816
PMCID:: PMC4294709

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000814202.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This variant has not been reported in the literature in individuals affected with MLH1-related conditions. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 422508). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu23Glyfs*8) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 1, 2024

ClinVar

Relating variation to medicine